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US Patent Application 20100063044 - SUBSTITUTED ANILINE DERIVATIVES

Application 20100063044 Filed on August 17, 2009. Published on March 11, 2010

Inventors

Assignee

US Classes

514/231.2, Morpholines (i.e., fully hydrogenated 1,4- oxazines)564/218, Benzene ring in a substituent E560/24, Carbamic acid558/241, Benzene ring bonded directly to the nitrogen or to the sulfur of a -C(=O)S- group544/335, Chalcogen attached indirectly to the diazine ring by nonionic bonding546/290, Chalcogen bonded directly to ring carbon of the six-membered hetero ring549/29, The hetero ring is five-membered549/72, Nitrogen or chalcogen attached indirectly to the hetero ring by nonionic bonding544/106, Morpholines (i.e., fully hydrogenated 1,4-oxazines514/625, R is acyclic514/277, Hetero ring is six-membered consisting of one nitrogen and five carbon atoms514/438The hetero ring is five-membered

Attorney, Agent or Firm

Foreign Documents

  • PA200401394 DK 09/13/2004

International Classes

A61K 31/167
C07C 233/01
C07C 271/28
C07C 333/08
C07D 239/02
C07D 213/63
C07D 333/02
C07D 333/22
C07D 265/30
A61P 25/00
A61P 25/22
A61P 25/06
A61P 25/30
A61K 31/5375
A61K 31/44
A61K 31/381


Claims


1. A compound having the general formula I: ##STR00019## wherein:Z is O or S;q is 1;R1 and R2 are each independently selected from the group consisting of halogen, cyano, amino, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl, Aryl, Heteroaryl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, and C3-8-heterocycloalk(en)yloxy;R3 is selected from the group consisting of C1-8-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn- )yl, Heteroaryl-C1-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl, Heteroaryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, amino-C1-6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl- , halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; andR4 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl, Aryl, Heteroaryl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C3-8-heterocycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(- en/yn)yl, NR5R.sup.6 and R7NH--C1-6-alk(en/yn)yl; wherein;R5 and R6 are each independently selected from the group consisting of hydrogen, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Heteroaryl-C1-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl and Heteroaryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, with the proviso that R5 and R6 can not both be hydrogen; andR7 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl and Heteroaryl;orZ is O or S;q is 0;R1 and R2 are each independently selected from the group consisting of C3-8-heterocycloalk(en)yl, Heteroaryl, and C3-8-heterocycloalk(en)yloxy;R3 is selected from the group consisting of C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn- )yl, Heteroaryl-C1-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl, and Heteroaryl-C3-8-cycloalk(en)yl-C1-16-alk(en/yn)yl; andR4 is selected from the group consisting of C3-8-heterocycloalk(en)yl, Heteroaryl, Aryl-C3-8-heterocycloalk(en)yl, halo-C1-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(- en/yn)yl, NR5R.sup.6 and R7NH--C1-6-alk(en/yn)yl; wherein:R5 and R6 are each independently selected from the group consisting of Heteroaryl-C1-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl and Heteroaryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl andR7 is Heteroaryl; ora pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1 and R2 are each independently selected from the group consisting of halogen, amino, C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and halo-C1-6-alk(en/yn)yl.

3. The compound according to claim 1, wherein q is 0.

4. The compound according to claim 1, wherein q is 1.

5. The compound according to claim 4, wherein Z is an oxygen atom.

6. The compound according to claim 1, wherein R3 is selected from the group consisting of C1-8-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Heteroaryl-C1-6-alk(en/yn)yl and amino-C1-6-alk(en/yn)yl.

7. The compound according to claim 1, wherein R4 is selected from the group consisting of halogen, C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl, Heteroaryl, Aryl-C3-8-heterocycloalk(en)yl, NR5R.sup.6 and R7NH--C1-6-alk(en/yn)yl, wherein R5, R6 and R7 are as previously defined.

8. The compound according to claim 7, wherein R4 is NR5R.sup.6 and R5 and R6 are each independently selected from the group consisting of hydrogen, Aryl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl and Heteroaryl-C1-6-alk(en/yn)yl with the proviso that R5 and R6 cannot both be hydrogen.

9. The compound according to claim 7, wherein R4 is R7NH--C1-6-alk(en/yn)yl and R7 is Aryl.

10. The compound according to claim 1, wherein any Aryl is optionally substituted with one or more substituents independently selected from the group consisting of amino, halogen, cyano, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, hydroxy, C1-6-alk(en/yn)yloxy, halo-C1-6-alk(en/yn)yloxy, di-(C1-6-alk(en/yn)yl)amino, C1-6-alk(en/yn)yl-CO--NH-- and C1-6-alk(en/yn)yl-sulfonamide; or two adjacent substituents may together with the Aryl group to which they are attached form a 4-8 membered ring, which optionally contains one or two heteroatoms and is optionally substituted with one or more C1-6-alk(en/yn)yl groups.

11. The compound according to claim 1, wherein any Heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl, Aryl, C1-6-alk(en/yn)yloxy and C1-6-alk(en/yn)yl-phenoxy.

12. The compound according to claim 1, wherein the compound is being selected from the group consisting of:N-(4-Bromo-2,6-dimethyl-phenyl)-2-thiophen-2-yl-acetamide,2-Bicyclo[2.- 2.1]hept-2-yl-N-(2,4-difluoro-6-morpholin-4-yl-phenyl)-acetamide,2-Cyclope- ntyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-phen- yl}-acetamide,N-(4-Azepan-1-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamid- e,2-Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-1-yl-phenyl)-acetamide,N-(2,4-Dim- ethyl-6-quinolin-3-yl-phenyl)-2-(4-fluoro-phenyl)-acetamide,N-[2-(2,3-Dihy- dro-benzo[1,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(4-fluoro-phenyl)-acetam- ide,N-[2,4-Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl)-phenyl- ]-2-(4-fluoro-phenyl)-acetamide,{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-- 2,6-dimethyl-phenyl}-carbamic acid propyl ester,[4-(4-Fluoro-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester,[2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester,[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-ca- rbamic acid propyl ester,{2,6-Dimethyl-4-[(4-methyl-2-phenyl-pyrimidin-5-ylmethyl)-amino]-ph- enyl}-carbamic acid propyl ester,{2,6-Dimethyl-4-[(6-p-tolyloxy-pyridin-3-ylmethyl)-amino]-phenyl}-c- arbamic acid propyl ester,{4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carb- amic acid propyl ester,{4-[(3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-2,6-dimethyl-- phenyl}-carbamic acid propyl ester,2-Cyclopentyl-N-{2,6-dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmet- hyl)-amino]-phenyl}-acetamide,N-{2,6-Dimethyl-4-[(6-trifluoromethyl-pyridi- n-3-ylmethyl)-amino]-phenyl}-3,3-dimethyl-butyramide,N-{2-Bromo-4-[(5-chlo- ro-thiophen-2-ylmethyl)-amino]-6-trifluoromethyl-phenyl}-3-cyclohexyl-prop- ionamide,{4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid ethyl ester,{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-ca- rbamic acid ethyl ester,{4-[(4-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-ca- rbamic acid propyl ester,{4-[(3,5-Difluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbami- c acid propyl ester,{4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester,N-(4-Bromo-2-methyl-6-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramid- e,{4-[(4-Methoxyphenylamino)-methyl]-2,6-dimethylphenyl}-carbamic acid propyl ester,{2,6-Dimethyl-4-[(4-trifluoromethylphenylamino)-methyl]-phen- yl}-carbamic acid 2-methoxyethyl ester,N-{4-[(5-Chloro-pyridin-2-ylamino)-methyl]-2,6-dimethylphenyl}-2-cy- clopentylacetamide,2-Cyclopentyl-N-{4-[(2,6-dichloro-pyridin-4-ylamino)-me- thyl]-2,6-dimethylphenyl}-acetamide,N-{2-Chloro-6-methyl-4-[(6-trifluorome- thyl-pyridin-3-ylmethyl)-amino]-phenyl}-2-(3-fluoro-phenyl)-acetamide,3,3-- Dimethyl-N-[2-methyl-6-morpholin-4-yl-4-(4-trifluoromethylbenzylamino)-phe- nyl]-butyramide, and2-Cyclopentyl-N-{2,6-dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-- methyl]-phenyl}-acetamide; ora pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents; and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

14. A method of increasing ion flow in a potassium channel of a mammal, the method comprising administering the composition of claim 13 to the mammal.

15. The method according to claim 14, wherein the method is for the treatment of a disorder or disease being responsive to an increased ion flow in a potassium channel, and a therapeutically effective amount of the composition is administered.

16. The method according to claim 15, wherein the disorder or disease to be treated is selected from the group consisting of a seizure disorder, an anxiety disorder, a neuropathic pain disorder, a migraine pain disorder, a neurodegenerative disorder, stroke, cocaine abuse, nicotine withdrawal, ethanol withdrawal and tinnitus.

17. The method according to claim 16, wherein the seizure disorder is selected from the group consisting of acute seizure, convulsion, status epilepticus, epilepsy, an epileptic syndrome and an epileptic seizure.

18. The method according to claim 16, wherein the anxiety disorder is selected from the group consisting of anxiety, a disease or disorder related to panic attack, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, a phobia, obsessive-compulsive disorder, post-traumatic stress disorder, an acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, separation anxiety disorder, an adjustment disorder, performance anxiety, a hypochondriacal disorder disorders, an anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified.

19. The method according to claim 16, wherein the neuropathic pain disorder and migraine pain disorder is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to trigeminal neuralgia and neupathic pain related to migraine.

20. The method according to claim 16, wherein the neurodegenerative disorder is e selected from the group consisting of Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob's disease, Parkinson's disease, an encephalopathy induced by AIDS, an encephalopathy induced by rubella viruses, a herpes virus, borrelia, a trauma-induced neurodegeneration, a neuronal hyperexcitation state and a neurodegenerative disease of the peripheral nervous system.

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